Studies have shown that proper pelvic physiologic function requires the coordination of complex integrative sensory pathways. These pathways may converge peripherally, centrally, or both (see Ustinova, E., et al. NEUROUROLOGY AND URODYNAMICS 29, 2010, 77-81). Sensitized convergent pelvic afferent pathways have been demonstrated in animal models of colitis and cystitis where inducing an inflammatory disease state in one organ produced lower sensory thresholds in the other. For example, the elimination of pain in one organ, such as the bladder, may reduce the pain in another organ.
Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a urological condition characterized by pain, increased urinary frequency, and urgency. This condition may also involve varying degrees of urinary incontinence and sexual dysfunction. IC/BPS include patients with urinary pain not attributable to other causes, such as infection or urinary stones, and are estimated to affect approximately 3 to 8 million people in the U.S. alone, the majority of whom are women (Berry 2009). IC/BPS is a serious condition with unmet medical needs.
There is also a need to treat pelvic pain, including bladder pain, levator ani syndrome, and irritative voiding symptoms in non-IC/BPS patients. Non-limiting examples of such non-IC/BPS patients include patients with ureteral stents or neurogenic conditions.
In addition, there is a need to treat chronic pelvic pain, vulvodynia, irritable bowel syndrome, and dyspareunia, among other pelvic pain disorders. High rates of comorbidities are found in IC/BPS patients.
Current treatments for pelvic pain, including bladder pain, include but are not limited to oral medications, such as antimuscarinics, alpha blockers, tricyclics antidepressents, antispasmodics, SSRIs, pentosan polysulfate sodium, and gabapentin. These drugs may not be effective for some patients. In addition, these oral drugs are delivered systemically, which may cause unwanted side effects and may not achieve therapeutically effective levels in the bladder when at acceptable plasma levels.
Another current treatment includes instillation of a drug (e.g., lidocaine, other “caine” anesthetic agents) solution directly into the bladder. Other instillations, such as dimethyl sulfoxide (DMSO), antimuscarinics, heparin, are also known. Another available procedure is hydrodistention. Botox injection or instillation is also available. None of these treatments have been shown to be widely effective or to provide a sustained therapeutic benefit.
A number of studies of instillation procedures with lidocaine have been performed in recent years. Nickel et al., BJU International, 103:910-918 (2008) discloses a study in which patients with IC/PBS were studied in a randomized, placebo controlled, double blind fashion, evaluating the effect of 5 daily instillations of an alkalinized solution of lidocaine (200 mg) on efficacy measures of bladder pain and irritative voiding symptoms on Day 8 (three days after completion of treatment) and Day 15 (ten days after completion of treatment.) One efficacy measure that showed improvement at Day 8 (the Interstitial Cystitis Symptom Index or ICSI) did not show sustained improvement at Day 15. Other efficacy measures (bladder pain, urgency, voiding frequency) never showed improvement following treatment when measured either at Day 8 and Day 15 (bladder pain) or only at Day 15 (urgency, voiding frequency). One efficacy measure called the Interstitial Cystitis Problem Index (ICPI) showed improvement both at Day 8 and Day 15, but the effect at Day 15 had diminished somewhat. These findings suggest that instillations of lidocaine into the bladder, even when administered on an aggressive schedule of daily instillation, were not able to show a sustained treatment effect out to 10 days following treatment.
Parsons, Urology 65(1):45-48 (2005) discloses a study in which patients with IC were treated with instillations of alkalinized lidocaine and heparin into the bladder as a single one hour treatment, then followed for 48 hours to assess duration of effect. The paper describes that 94% of patients had relief at 20 minutes following instillation, 50% at 4 hours and 3 of 28 patients (FIG. 1) or ˜10% at 48 hours, suggesting a waning of effect over time. Additionally, a set of patients who received three instillations a week for two weeks were assessed at 48 hours following last treatment for durability of effect; 80% reported relief of symptoms; no further follow-up is provided. These findings suggest that the durability of treatment effect for a single lidocaine instillation is approximately 10% at 48 hours.
Henry, et al., J Urology 165:1900-03 (2001) discloses a study in which lidocaine instillations were used in both healthy volunteers (for pharmacokinetic purposes) and IC patients. Pain assessments following a single lidocaine instillation showed duration of effect to be approximately 24 hours: the mean pain score prior to treatment was 6.0 Immediately following treatment this decreased to 1.8. The next day, mean pain had increased up to 3.7. This was again reduced to 1.2 with a second instillation. These results support those seen in the Parsons and Nickel publications, suggesting that the duration of treatment effect with intravesical solutions of lidocaine are 24 to 48 hours.
It would be desirable to provide improved methods for treating patients suffering from IC/BPS, chronic pelvic pain, vulvodynia, irritable bowel syndrome, levator ani syndrome, dyspareunia, or combinations of these conditions. It would also be desirable to treat other types of pelvic pain. It would be desirable to provide a sustained treatment effect for several days or weeks or more beyond the active treatment period and beyond the local treatment site. It would also be desirable to reduce the number of invasive procedures, such as instillation procedures, needed to achieve a sustained treatment effect, in particular while reducing the side effects associated with systemic administration of drugs that are potentially effective in treating one or more of the foregoing pelvic disorders.